Compounds used to disinfect ocular prostheses such as contact lenses or employed to preserve ophthalmic formulations designed to be applied directly to the eye or to objects which are in direct contact with the eyes, must be non-irritating and free of any detrimental side effects. Yet, they must be sufficiently effective against bacteria and fungi to ensure the sterility of such prostheses or guarantee a reasonable shelf-life of the ophthalmic formulations and thereby prevent infections. The inherent conflict between antimicrobial efficiency on the one hand, and non-irritancy on the other has lead to compromises. The conventional microbial agents which can be found in ophthalmic formulations comprise:
Benzalkonium chloride, benzethonium chloride, benzyl alcohol, chlorobutanol, chlorhexidine digluconate or diacetate, methyl and propyl hydroxybenzoate (parabens), phenylethyl alcohol, phenylmercuric acetate or nitrate, sorbic acid, and thimerosal.
Presently there are two polymeric preservatives used in ophthalmic products under the trademarks of "Polyquad" and "Dymed". "Polyquad". Polyquad is alpha-4[1-tris(2-hydroxyethyl) ammonium chloride-2-dibutenyl] poly[1-dimethyl ammonium chloride-2-dibutenyl]-.omega.-tris (2-hydroxyethyl) ammonium chloride. Dymed brand is poly[aminopropyl-bis(biguanide)] or poly[hexamethylene-bis(biguanide)] and has a lower molecular weight, and hence, is a considerably smaller molecule. Although non-irritating, neither compound is effectively fungicidal at the concentrations employed in ophthalmic formulations and both compounds require additional agents to achieve such an effect.
Some attributes of a disinfectant/preservative, which would be very desirable from an ophthalmic point of view, are:
1) Bactericidal and fungicidal activity at concentration levels which are much lower than those likely to cause damage to mammalian cells, i.e. selective toxicity. PA1 2) Nonirritant to the ocular surface upon topical application. PA1 3) Innocuous toward corneal epithelial or endothelial cells. PA1 4) Effective in the physiological pH range, i.e. pH 6 -8. PA1 5) Not acting as a sensitizing agent to ocular tissues unlike thimerosal and chlorhexidine. PA1 6) Readily soluble in aqueous solution. PA1 7) Chemically and thermally stable in aqueous solution and able to withstand autoclaving (20 minutes at 120 degrees centigrade). PA1 8) Possessing prolonged chemical stability in aqueous solution at physiological pH's (acceptable shelf-life). PA1 9) Not absorbed into the polymer matrix of hydrogel lenses thereby not accumulating within the matrix of the lens nor leaching into the ocular tissues upon application of the lens to the eye. PA1 10) Not adsorbed adversely onto the surface of the contact lenses, so as to diminish the water wettability of such lenses, nor increases the water/lens interfacial tension appreciably and thereby reduce lens ocular compatibility and perceived in-eye comfort. PA1 11) Not interfering with the solubility or other properties of the components of the ocular formulation to be preserved such as contact lens wetting, film forming, and viscosity-modifying agents or therapeutic agents. PA1 12) Neither absorbed into nor adsorbed onto the polymers used in the construction of eye-dropper containers (bottles). PA1 13) Not absorbed systemically, i.e. by the bodily organs via the circulatory system. PA1 14) Free of toxic heavy metal ions which may act as cumulative poisons in the body.
It is important to note here that none of the earlier listed presently available preservatives fulfill all of the above criteria especially those listed as items 9 and 10.
The monomeric antibacterial agents listed earlier cannot be added to ophthalmic formulations likely to be used by patients who wear hydrogel contact lenses because the small molecular size of these agents enable them to penetrate pores of hydrogels, the polymeric matrices of the hydrogel materials. The antimicrobial agent accumulated within the lens matrix would eventually leach into the tear film upon application of the lens to the eye. The pore size in poly(hydroxyethylmethacrylate) [poly(HEMA)] gels used in the fabrication of hydrogel lenses is approximately 30-50 Angstroms, as reported in Hydrogels in Medicine and Pharmacy, Vol. II, Polymers. Ed. Peppas, N. K., CRC Press, Inc. To prevent the absorption of antimicrobial agents into such lenses the use of polymeric anti-microbial agents has been suggested namely by Andrews, J. K. in U.S. Pat. No. 4,304,894 and Stark, R. L. in U.S. Pat. No. 4,407,791.
Until recently, virtually all of the commercially available hydrogel lenses were fabricated from neutral polymeric materials such as poly(HEMA). However, the introduction of disposable lenses, such as those sold under the trademark name "Acuvue" by Johnson and Johnson, Inc., has led to the reintroduction and widespread use of a contact lens material fabricated by the anionic Etafilcon A and containing methylmethacrylic acid groups. Such lenses are not ideally suited for use with ophthalmic solutions containing polyquaternary ammonium antimicrobial agents, since the latter agents react electrostatically with the surfaces of such materials.
Clinical impressions suggest that such polyquaternary ammonium disinfectant solutions do indeed adsorb to the surfaces of certain soft lens materials, especially anionic materials, and cause ocular discomfort. It is essential for the lens to retain its wettability and low interfacial tension against tear, and allow a continuous film of tear fluid covering, in order to remain acceptable to the contact lens wearer.
Interaction between the positively charged hydrophilic polyquaternary ammonium groups of anti-bacterials and anionic lenses causes the lens surface to become covered with a layer of hydrophobic polymer and may lead to dewetting. Hence, agents which act to lower the critical surface tension of a contact lens should be avoided when formulating ophthalmic products used for disinfecting, cleaning, cushioning, and reconditioning contact lenses or in ophthalmic medications likely to be used in patients who wear contact lenses, e.g. artificial tears and vasocon-strictors.
Ellis, E. J. et al U.S. Pat. Nos. 4,168,112 and 4,436,730 disclose the treatment of hard and soft contact lens materials bearing a surface electric charge with a solution comprising hydrophilic polymers possessing an opposite charge in order to form a layer of hydrophilic polyelectrolyte complex and enhance surface wettability. These patents teach the use of polyionene polymers and cationic polyethylene imine to that effect. However, they do not teach the use of the polyionene copolymer, or the use of copolymers formed from cationic and nonionic monomeric components, nor do they teach dimethylimino ethylene as a cationic monomer, either as part of the homo or co-polymer as will be disclosed below.
The results of comparative tests set out in Table IV below indicate that the polyionene present in Polyquad does not facilitate the wetting of contact lens surfaces. Therefore, the disclosure by Ellis et al that polyionenes as a group may be considered as useful agents for facilitating the wetting of anionically charged contact lens matrices including soft lenses is not supported. We found that only particular polyionenes possess the ability to wet the surface of anionically charged contact lens surfaces well. It is never obvious from the molecular structure which polyionene is likely to possess this coveted property. Structure-activity relationship of copolymers cannot be directly-inferred from the functional properties of their monomeric constituents due to the potential for multiple orientations within such large molecules. This can only be defined experimentally. Hence, it is not evident, and indeed undefined, in the disclosure of Ellis which polyionenes are capable for facilitating the wetting of contact lenses.
The homopolymer of ethylene oxide is cited as a means of wetting anionic surfaces by Ellis et al in U.S. Pat. No. 4,321,261 but only by means of hydrogen bonding and not, as we found, as part of a copolymer combined with a cationic monomer where the molecular binding to lens occurs electrostatically.
The disclosures made by Ellis et al are solely concerned with the use of polycationic polymers, including polyquaternary polymers and polyionenes as a means of enhancing the wettability of contact lenses and do not suggest that they may act additionally as antimicrobial agents in ophthalmic solutions such as contact lens care solutions. The presence of accepted ophthalmic preservative agents, such as benzalkonium chloride, in the formulations shown in the examples of the cited patents of Ellis et al further indicate that said invention relates solely to a means of wetting contact lenses. Furthermore, it is not recognized by the inventors that certain polyquaternary agents such as benzalkonium chloride at low concentrations may act as dewetting agents, i.e. they convey to the solid surface hydrophobic properties.
In comparison we have found that the polyionene in certain compositions surprisingly possesses both antimicrobial properties and an ability to enhance rather than diminish the wetting characteristics of contact lenses especially the anionically charged lens surfaces, and thus offers unique advantages over the previously listed disinfectants and preservatives which are conventionally used in ophthalmic formulations.
Although, Stark, R. L. expressly teaches the use of a polyionene antimicrobial agent for disinfecting contact lenses and preserving ophthalmic solutions including ophthalmic medicaments in U.S. Pat. No. 4,407,791, ("Polyquad brand") and Ogunbiyi et al expressly teach the use of a polymeric biguanide as a method of disinfecting contact lenses in U.S. Pat. No. 4,836,986 ("Dymed"), neither patent teaches or suggests the use of the polymer described in the present invention.
While there may be many industrial and even pharmaceutical disinfectants and preservatives available, their suitability to ophthalmic applications is never obvious and their potential must be first recognized, then carefully formulated and clinically tested to achieve a satisfactory balance of efficacy, safety and contact lens compatibility.